Potassium channels are transmembrane proteins which are ubiquitously expressed in mammalian cells and represent one of the largest and the most diverse group of ion channels from a molecular perspective. Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are largely regulated by voltage, cell metabolism, calcium and receptor mediated processes. [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21; and Quast, U., et al., Trends in Pharmacol. Sciences (1989), 10, 431]. Calcium-activated potassium (Kca) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of Kca channels is regulated by intracellular [Ca2+], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K+ solutions, Kca channels are divided into three subclasses: large conductance (also referred to in the art as “BK” or “Maxi-K”), having a conductance of greater than about 150 picosemens (“pS”); intermediate conductance, having a conductance of about 50-150 pS; and small conductance, having a conductance of less than about 50 pS. Large-conductance calcium-activated potassium channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. et al., Pflugers Archiv. (1987) 408,98; Baro, I., et al., Pflugers Archiv. (1989) 414 (Suppl. 1), S168; and Ahmed, F. et al., Br. J. Pharmacol. (1984) 83, 227].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and maintain the transmembrane voltage near the K+ equilibrium potential (“Ek”) of about −90 milliVolts (“mV”). It has been shown that opening of potassium channels shift the cell membrane potential towards the Ek, resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, 21]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. BK channels which are regulated by both voltage and intracellular Ca2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells, as well as other types of cells, e.g., cardiac cells. [Xu, W., Liu, Y., Wang, S., McDonald, T., Van Eyk, J. E., Sidor, A., and O'Rourke, B. (2002) Cytoprotective Role of Ca2+-activated K+ Channels in the Cardiac Inner Mitochondrial Membrane. Science 298, 1029-1033].
A variety of synthetic and naturally occurring compounds with BK opening activity have been reported. Of particular interest are 4-aryl-3-hydroxyquinolin-2-one derivatives disclosed, for example, in U.S. Pat. No. 5,892,045, issued Apr. 6, 1999, U.S. Pat. No. 5,922,735, issued Jul. 13, 1999, U.S. Pat. No. 6,353,119, issued Mar. 5, 2002.
Despite the advances in the art made possible by the 4-aryl-3-hydroxyquinolin-2 one derivatives noted above, further advances are desired in the class of compounds capable of modulating potassium channels, in particular, large-conductance calcium-activated potassium channels. Desirably, such compounds would be useful in treating conditions arising from dysfunction of cellular membrane polarization and conductance.